rs1058164

Positions:

• chr22-42129130-C-G
• chr22-42129130-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000106.6(CYP2D6):​c.408G>C​(p.Val136Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 150,534 control chromosomes in the GnomAD database, including 26,082 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.57 (26082 hom., cov: 34)
  • Exomes 𝑓: 0.52 (196805 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP2D6 NM_000106.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.58

Genes affected

CYP2D6 (HGNC:2625): (cytochrome P450 family 2 subfamily D member 6) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and is known to metabolize as many as 25% of commonly prescribed drugs. Its substrates include antidepressants, antipsychotics, analgesics and antitussives, beta adrenergic blocking agents, antiarrythmics and antiemetics. The gene is highly polymorphic in the human population; certain alleles result in the poor metabolizer phenotype, characterized by a decreased ability to metabolize the enzyme's substrates. Some individuals with the poor metabolizer phenotype have no functional protein since they carry 2 null alleles whereas in other individuals the gene is absent. This gene can vary in copy number and individuals with the ultrarapid metabolizer phenotype can have 3 or more active copies of the gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

CYP2D6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 22-42129130-C-G is Benign according to our data. Variant chr22-42129130-C-G is described in Lovd as [Benign]. Variant chr22-42129130-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2D6	NM_000106.6	c.408G>C	p.Val136Val	synonymous_variant	3/9	ENST00000645361.2	NP_000097.3
CYP2D6	NM_001025161.3	c.353-186G>C		intron_variant			NP_001020332.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2D6	ENST00000645361.2	c.408G>C	p.Val136Val	synonymous_variant	3/9		NM_000106.6	ENSP00000496150.1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86080 AN: 150426 Hom.: 26052 Cov.: 34

Gnomad AFR AF: 0.638

Gnomad AMI AF: 0.517

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.558

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.525 AC: 752046 AN: 1433080 Hom.: 196805 Cov.: 69 AF XY: 0.527 AC XY: 376050 AN XY: 713826

Gnomad4 AFR exome AF: 0.624

Gnomad4 AMR exome AF: 0.396

Gnomad4 ASJ exome AF: 0.635

Gnomad4 EAS exome AF: 0.622

Gnomad4 SAS exome AF: 0.532

Gnomad4 FIN exome AF: 0.491

Gnomad4 NFE exome AF: 0.521

Gnomad4 OTH exome AF: 0.547

GnomAD4 genome AF: 0.572 AC: 86147 AN: 150534 Hom.: 26082 Cov.: 34 AF XY: 0.568 AC XY: 41805 AN XY: 73540

Gnomad4 AFR AF: 0.638

Gnomad4 AMR AF: 0.488

Gnomad4 ASJ AF: 0.638

Gnomad4 EAS AF: 0.689

Gnomad4 SAS AF: 0.554

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.553

Gnomad4 OTH AF: 0.553

Alfa AF: 0.576 Hom.: 4799

Bravo AF: 0.575

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1058164; hg19: chr22-42525132;